Medicinal aerosol products containing formulations of ciclesonide and related steroids

ABSTRACT

A pharmaceutical aerosol formulation suitable for oral and/or nasal inhalation including an anti-inflammatory steroid of the formula ##STR1## in which: R 1  is 1-butyl, 2-butyl, cyclohexyl or phenyl and 
     R 2  is acetyl or isobutanoyl, in particular ciclesonide. The formulations also include hydrofluorocarbon propellants such as HFC 134a and/or 227, and cosolvent such as ethanol in an amount sufficient to solubilize the ciclesonide or related steroid (and various optional ingredients, such as surfactant). The formulations exhibit very desirable physical and chemical stability, as well as excellent delivery characteristics.

This application claims priority under 35 U.S.C. 119 to GB 9710496.2,filed May 21, 1997, and GB 9803990.2, filed Feb. 25, 1998.

FIELD

This invention relates to medicinal aerosol products and in particularto medicinal products containing apregna-1,4,diene-3,20-dione-16-17-acetal-21 ester, suitable foradministration by inhalation.

BACKGROUND

GB-2247680 discloses pregna-1,4-diene-3,20-dione-16-17-acetal-21 estersand their use in the treatment of inflammatory conditions.

The compounds have the general structure: ##STR2## wherein R₁ is2-propyl, 1-butyl, 2-butyl, cyclohexyl or phenyl; and R₂ is acetyl orisobutanoyl.

Ciclesonide is 11β, 16α, 17, 21-tetrahydroxypregna 1,4-diene-3,20-dione,cyclic 16,17-acetal with cyclohexanecarboxaldehyde, 21-isobutyratehaving the structure of formula (I) without fluorine atoms and in whichR₁ is cyclohexyl and R₂ is isobutanoyl. This compound has undergoneevaluation as an antiasthmatic and pharmacokinetic studies show that itwill be useful in an inhaler formulation. Ciclesonide is only moderatelyabsorbed after oral administration and has low systemic activity.Concentration of the drug in the lungs is high and metabolism by liveroxidases is very high, giving the drug a low plasma half-life. Systemicactivity of ciclesonide is three times lower than that of budes onidebut anti-inflammatory activity is higher for the former.

GB-2247680 proposes a specific pressurized aerosol formulation fordelivering ciclesonide for oral and nasal inhalation. The disclosedformulation consists of ciclesonide as a micronized suspension ofparticles, sorbitan trioleate surfactant, and a mixture of three CFCpropellants: trichloro-fluoromethane, dichlorotetrafluoromethane, anddichlorodifluoromethane. However these CFC propellants are now believedto provoke the degradation of stratospheric ozone and there is a need toprovide aerosol formulations for medicaments which employ so-called"ozone-friendly" propellants.

A class of propellants which are believed to have minimalozone-depleting effects in comparison to conventionalchlorofluorocarbons comprise hydrofluorocarbons and a number ofmedicinal aerosol formulations using such propellant systems aredisclosed in, for example, EP 0372777, W091/04011, W091/11173,W091/11495, W091/14422, W093/11743, and EP-0553298 (all herebyincorporated by reference). These applications are all concerned withthe preparation of pressurised aerosols for the administration ofmedicaments and seek to overcome problems associated with the use ofthis new class of propellants, in particular the problems of stabilityassociated with the pharmaceutical formulations prepared. Theapplications propose, for example, the addition of one or more ofadjuvants such as alcohols, alkanes, dimethyl ether, surfactants(including fluorinated and non-fluorinated surfactants, carboxylicacids, polyethoxylates etc.).

However, despite the various approaches used in formulating drugs foruse in aerosol inhalation, there are still many serious difficulties anduncertainties often encountered in attempting to develop a physicallyand chemically stable CFC-free formulation that reliably delivers anaccurate dose of drug having the proper particle size range. Inparticular, there is a need for a CFC-free medicinal aerosol productcontaining ciclesonide (or similar molecules) that is chemically andphysically stable and that is suitable for delivery to the respiratorysystem of a patient.

SUMMARY

It has now been surprisingly found that, rather than the prior artapproach of formulating ciclesonide as a suspension, ciclesonide can bevery beneficially formulated as a physically and chemically stablesolution in formulations including hydrofluorocarbon propellants.According to the present invention there is provided a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof the formula: ##STR3## in which: R₁ is 1-butyl, 2-butyl, cyclohexyl orphenyl and

R₂ is acetyl or isobutanoyl, and a hydrofluorocarbon propellant,preferably selected from 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoropropane and a mixture thereof, and cosolvent,preferably ethanol, in an amount effective to solubilize the compound offormula (I) and optionally a surfactant.

The compounds of formula (I) is preferably ciclesonide and is generallypresent at a concentration of from 1 to 8 mg/ml, preferably 1 to 5mg/ml.

The formulation generally comprises from 3 to 25% preferably 5 to 20%,more preferably 7 to 12% by weight ethanol.

The propellant preferably includes a hydrofluoroalkane, in particularPropellant 134a, Propellant 227 or a mixture thereof, generally at about50:50 w/w. More preferably the propellant consists of Propellant 134a.

The formulations may contain surfactant but are preferably free ofsurfactant. The formulations are preferably free of other excipients.

Preferred formulations consist of from 1 to 5 mg/ml ciclesonide, 8% byweight ethanol and Propellant 134a.

The formulations may be prepared by adding the required quantity of druginto an aerosol vial, crimping a valve on the vial and introducing apre-mixed blend of propellant and ethanol through the valve. The vial isplaced in an ultrasonic bath to ensure solubilisation of the drug.

Alternatively, the formulations may be prepared by preparing a drugconcentrate with ethanol and adding this concentrate to the pre-chilledpropellant in a batching vessel. The resulting formulation is filledinto vials.

The formulations may be filled in plastics, metal or glass vials.Suitable plastics materials include polyethyleneterephthalate; apreferred metal is aluminium.

The vials are equipped with a metered dose dispensing valve e.g.dispensing 50 μl with each actuation. A suitable metered dose dispensingvalve comprises a valve ferrule having a rim and associated rim gasketfor engaging the aerosol vial and an aperture therethrough;

a metering tank having walls defining an exterior, an internal meteringchamber, an inlet orifice, an inlet end, and an outlet end;

an elongate valve stem having a filling channel, a filling end, adischarge end, and a discharge orifice;

wherein the outlet end of the metering tank is in sealing engagementwith the valve ferrule, the discharge end of the valve stem passesthrough both the valve ferrule aperture and the outlet end of themetering tank and is in slidable sealing engagement with the valveferrule;

wherein the filling end of the valve stem passes through and is inslidable engagement with the inlet orifice of the metering tank, and abottle emptier surrounding the metering tank and filling end of theelongate valve stem and defining a passage between the metering tank andbottle emptier allowing communication between the inlet orifice of themetering tank and the aerosol vial;

wherein the valve stem is movable between an extended closed positionwherein the filling channel of the valve stem allows open communication,via the inlet orifice, between the interior and the exterior of themetering chamber, and wherein the outlet end of the metering tank isclosed, and a compressed open position wherein the inlet orifice of themetering tank is in ealing engagement with the filling end of the valvestem and the discharge orifice of the valve stem allows opencommunication between the interior and exterior of the metering chamber.

A suitable valve is commercially available under the trade nameSPRAYMISER.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described with reference to the accompanyingdrawings in which:

FIG. 1 represents a cross-section through a metered dose dispensingvalve suitable for use in the invention,

FIG. 2 represents a longitudinal cross-section through an adaptor foraccommodating an aerosol vial equipped with a metered dose dispensingvalve, in accordance with the invention,

FIG. 3 represents a front view of the adaptor shown in FIG. 2, and,

FIG. 4 represents a detailed section of the area X shown in FIG. 2.

DETAILED DESCRIPTION

The valve illustrated in FIG. 1 comprises a valve ferrule (2) and anassociated rim gasket (4) for engaging an aerosol vial. The rim gasket(4) may conveniently comprise an ethylene-butylene copolymer e.g. thecopolymer commercially available from Union Carbide under the trade nameFLEXOMER GERS 1085NT.

A metering tank (6) has walls defining a metering chamber (8) having aninlet end associated with a tank seal (10) and an outlet end associatedwith a diaphragm (12). An elongate valve stem (14) having a fillingchannel (16), a discharge end (18) and a discharge orifice (20) extendsthrough the valve ferrule and metering chamber in sealing engagementwith the diaphragm (12) and tank seal (10).

The tank seal and diaphragm may conveniently comprise abutadiene-acrylonitrile copolymer e.g. Type DB-218 commerciallyavailable from American Gasket & Rubber Company.

A bottle emptier (22) surround the metering tank (6) and valve stem suchthat a capillary channel (24) is defined between the metering tank andbottle emptier to allow passage of aerosol formulation from the aerosolvial to the inlet end of the metering chamber.

The valve stem (14) is movable between an extended closed positionwherein the filling channel (16) of the valve stem allows opencommunication, via the inlet orifice, between the interior and theexterior of the metering chamber, and wherein the outlet end of themetering tank is closed, and a compressed open position wherein theinlet orifice of the metering tank is in sealing engagement with thefilling end of the valve stem and the discharge orifice of the valvestem allows open communication between the interior and exterior of themetering chamber. The valve stem (14) is biased to the extended closedposition by spring (15).

FIGS. 2 to 4 illustrate a press-and-breathe adaptor for an aerosol vialequipped with dispensing valve suitable for use in the invention. Theadaptor comprises a body portion (30) and a mouthpiece (32). A pluralityof ribs (34) are positioned within the body portion (30) in order tolocate and support the aerosol vial (not shown) in the correct position.The dispensing end of the elongate valve stem of the metered dosedispensing valve is positioned within the nozzle block (36). The adaptoris made of polypropylene or high density polyethylene. However, toensure a good seal between the valve stem (14) and the central aperture(38), high density polyethylene is preferred.

As shown in FIG. 4 the nozzle block (36) comprises a central aperture(38) having a flared opening (40) to accommodate the valve stem. Thevalve stem is inserted until it abuts the ledge (42). In use, thepatient inserts the mouthpiece into the mouth and depresses the base ofthe aerosol vial while inhaling. The relative movement between theelongate valve stem and the metering tank causes the discharge orificeto enter the metering tank and the contents thereof are dispensed underpressure through the discharge end of the elongate valve stem to enterchamber (44) in the nozzle block (36) and exit through orifice (46). Aplume of droplets of respirable size is directed from the orifice (46)into the mouthpiece (32) for inhalation by the patient.

It has been found that the dimensions of the orifice (46) may have aprofound effect on the respirable fraction of the formulation dispensedfrom the mouthpiece of the adaptor. Both the jet length "l" and diameter"d" of the orifice (46) affect the delivery to the lung of theformulation. This is often assessed by an "in vitro" test which uses anAndersen Cascade Impactor, such as described in the U.S. Pharmacopoiea.An Andersen Respirable Dose is defined as the weight of drug deliveredto plates 3 to 7 and the filter of the impactor from a single actuationof the inhaler. The optimum dimensions are also dependent upon theparticular formulation to be dispensed. In general, medication deliveryincreases with increasing orifice diameter "d" and with increasing jetlength "l". However, the Anderson respirable dose increases withdecrease in orifice diameter "d".

The selection of particular dimensions of the nozzle orifice enables anAndersen Respirable Dose of greater than 120 micrograms to be achievedfor a product delivering 200 micrograms of ciclesonide per actuation exvalve, without significantly detracting from the Medication Delivery.Thus the patient potentially derives the benefit of a higher than usualproportion of dispensed drug reaching the lungs without excessivebuild-up of drug on the actuator or the product falling short ofregulatory stipulations.

For formulations containing from 5 to 10% by weight ethanol,particularly 8% by weight ethanol it has been found that good respirabledoses are achieved with an orifice diameter "d" within the range 0.20 to0.33 mm, preferably about 0.28 mm and a jet length "l" in the range 0.30to 0.60 mm preferably 0.50 mm.

The invention will now be illustrated by the following Examples:

In each Example, the percentage of ethanol in the ethanol/propellantblend is denoted in brackets.

EXAMPLE 1

    ______________________________________                                                     mg/ml                                                            ______________________________________                                               Ciclesonide                                                                             1.000                                                               Ethanol (5%)                                                                           67.800                                                               P227    1287.200                                                                      1356.000                                                       ______________________________________                                    

EXAMPLE 2

    ______________________________________                                                     mg/ml                                                            ______________________________________                                               Ciclesonide                                                                             5.000                                                               Ethanol (5%)                                                                           67.800                                                               P227    1283.200                                                                      1356.000                                                       ______________________________________                                    

EXAMPLE 3

    ______________________________________                                                     mg/ml                                                            ______________________________________                                        Ciclesonide     1.000                                                         Ethanol (20%)  244.800                                                        P227           978.200                                                                       1224.000                                                       ______________________________________                                    

EXAMPLE 4

    ______________________________________                                                     mg/ml                                                            ______________________________________                                        Ciclesonide     5.000                                                         Ethanol (20%)  244.800                                                        P227           974.200                                                                       1224.000                                                       ______________________________________                                    

EXAMPLE 5

    ______________________________________                                                     mg/ml                                                            ______________________________________                                               Ciclesonide                                                                             1.000                                                               Ethanol (7%)                                                                           82.740                                                               P134a   1098.260                                                                      1182.000                                                       ______________________________________                                    

EXAMPLE 6

    ______________________________________                                                     mg/ml                                                            ______________________________________                                               Ciclesonide                                                                             5.000                                                               Ethanol (7%)                                                                           82.740                                                               P134a   1094.260                                                                      1182.000                                                       ______________________________________                                    

EXAMPLE 7

    ______________________________________                                                     mg/ml                                                            ______________________________________                                        Ciclesonide     1.000                                                         Ethanol (20%)  220.800                                                        P134a          882.200                                                                       1104.000                                                       ______________________________________                                    

EXAMPLE 8

    ______________________________________                                                     mg/ml                                                            ______________________________________                                               Ciclesonide                                                                            5.000                                                                Ethanol (8%)                                                                          220.800                                                               P134a   878.200                                                                       1104.000                                                       ______________________________________                                    

EXAMPLE 9

    ______________________________________                                                    mg/ml                                                             ______________________________________                                        Ciclesonide    1.000                                                          Ethanol (8%)  102.160                                                         P227          586.920                                                         P134a         586.920                                                                       11277.000                                                       ______________________________________                                    

EXAMPLE 10

    ______________________________________                                                    mg/ml                                                             ______________________________________                                        Ciclesonide    5.000                                                          Ethanol (8%)  102.160                                                         P227          584.920                                                         P134a         584.920                                                                       11277.920                                                       ______________________________________                                    

EXAMPLE 11

    ______________________________________                                                     mg/ml                                                            ______________________________________                                               Ciclesonide                                                                             1.000                                                               Ethanol (12%)                                                                          126.500                                                              P227     568.750                                                              P134a    568.750                                                                       1265.000                                                      ______________________________________                                    

EXAMPLE 12

    ______________________________________                                                     mg/ml                                                            ______________________________________                                        Ciclesonide     5.000                                                         Ethanol (120i) 126.500                                                        P227           566.750                                                        P134a          566.750                                                                       1115.000                                                       ______________________________________                                    

EXAMPLE 13

    ______________________________________                                                     mg/ml                                                            ______________________________________                                               Ciclesonide                                                                             1.000                                                               Ethanol  94.800                                                               P134a   1090.200                                                                      1186.000                                                       ______________________________________                                    

EXAMPLE 14

    ______________________________________                                                     mg/ml                                                            ______________________________________                                               Ciclesonide                                                                             2.000                                                               Ethanol   94.7200                                                             P134a   1089.280                                                                      1186.000                                                       ______________________________________                                    

EXAMPLE 15

    ______________________________________                                                     mg/ml                                                            ______________________________________                                               Ciclesonide                                                                             4.000                                                               Ethanol   94.5600                                                             P134a   1087.440                                                                      1186.000                                                       ______________________________________                                    

EXAMPLE 16

    ______________________________________                                                     mg/ml                                                            ______________________________________                                               Ciclesonide                                                                             4.000                                                               oleic acid                                                                              0.237                                                               Ethanol  94.541                                                               P134a   1087.222                                                                      1186.000                                                       ______________________________________                                    

All of the formulations of Examples 1 to 15 were clear, colourlesssolutions in which the ciclesonide was completely solubilized.

Examples 13 to 15 were the subject of stability trials over severalmonths and proved to be physically and chemically stable.

Although the invention has been described in terms of preferredformulations and ingredients, it will be understood that these are notintended to be limiting. To the contrary, those skilled in the art willunderstand that various optional ingredients may be included, such asflavoring agents, preservatives, additional active ingredients, and thelike, while still embodying the present invention.

We claim:
 1. A pharmaceutical aerosol product comprising an aerosol vialequipped with a dispensing valve and containing an aerosol formulationsuitable for oral or nasal inhalation comprising a therapeuticallyeffective amount of a dissolved compound of the formula: ##STR4## inwhich: R₁ is 1-butyl, 2-butyl, cyclohexyl or phenyl andR₂ is acetyl orisobutanoyl, and a propellant selected from the group consisting of1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and amixture thereof, and cosolvent in an amount effective to solubilize thecompound of formula (I) and optionally a surfactant.
 2. A pharmaceuticalcomposition as claimed in claim 1 in which the valve is a metered dosedispensing valve.
 3. A pharmaceutical composition as claimed in claim 2in which the valve comprises a valve ferrule having a rim and associatedrim gasket for engaging the aerosol vial and an aperture therethrough;ametering tank having walls defining an exterior, an internal meteringchamber, an inlet orifice, an inlet end, and an outlet end; an elongatevalve stem having a filling channel, a filling end, a discharge end, anda discharge orifice; wherein the outlet end of the metering tank is insealing engagement with the valve ferrule, the discharge end of thevalve stem passes through both the valve ferrule aperture and the outletend of the metering tank and is in slidable sealing engagement with thevalve ferrule; wherein the filling end of the valve stem passes throughand is in slidable engagement with the inlet orifice of the meteringtank, and a bottle emptier surrounding the metering tank and filling endof the elongate valve stem and defining a passage between the meteringtank and bottle emptier allowing communication between the inlet orificeof the metering tank and the aerosol vial; wherein the valve stem ismovable between an extended closed position wherein the filling channelof the valve stem allows open communication, via the inlet orifice,between the interior and the exterior of the metering chamber, andwherein the outlet end of the metering tank is closed, and a compressedopen position wherein the inlet orifice of the metering tank is insealing engagement with the filling end of the valve stem and thedischarge orifice of the valve stem allows open communication betweenthe interior and exterior of the metering chamber.
 4. A pharmaceuticalproduct as claimed in claim 3 additionally comprising an adapter havinga body for containing the aerosol vial, a nozzle block accommodating thedischarge end of the valve stem and a mouthpiece.
 5. A pharmaceuticalproduct as claimed in claim 4 in which the nozzle block has an exitorifice directed towards the mouthpiece, the exit orifice having adiameter in the range 0.20 to 0.33 mm.
 6. A pharmaceutical product asclaimed in claim 5 in which the exit orifice has a diameter of about0.28 mm.
 7. A pharmaceutical product as claimed in claim 6 in which theexit orifice has a jet length in the range 0.30 to 0.60 mm.
 8. Apharmaceutical product as claimed in claim 7 in which the exit orificehas a jet length of 0.50 mm.